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Alnylam Advances Development Candidate for ALN-AAT, a Subcutaneously Administered RNAi Therapeutic Targeting Alpha-1 Antitrypsin (AAT) in Development for the Treatment of AAT Deficiency-Associated Liver Disease

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Company Plans to File Investigational New Drug (IND) Application in mid-2015, Positioning ALN-AAT as the Seventh Clinical Program as Part of the Company’s Up-Scaled “Alnylam 5x15” Guidance

May 6, 2014

Alnylam Pharmaceuticals, Inc., a leading RNAi therapeutics company, announced today that it is advancing its Development Candidate (DC) for ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) in development for the treatment of AAT deficiency-associated liver disease. New pre-clinical data were presented in a Late-Breaking Abstract Session at Digestive Disease Week (DDW), held May 3 – 6, 2014 in Chicago, Illinois. ALN-AAT is one of Alnylam’s genetic medicine programs, which are RNAi therapeutics directed toward genetically defined targets for the treatment of diseases with high unmet medical need. AAT deficiency-associated liver disease is caused by accumulation of mutant AAT protein (“Z-allele” or “Z-AAT”) in liver tissue with subsequent liver injury, fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma. It is estimated that approximately 12,000 people with AAT deficiency in the U.S. and E.U. have associated liver pathology. The company now plans to initiate IND-enabling studies with the goal of filing an IND or IND equivalent for ALN-AAT in mid-2015.

“Our pre-clinical research efforts have now led to the selection of a DC in our ALN-AAT program, which is part of our genetic medicine pipeline. This is important progress since we believe ALN-AAT holds considerable promise as a novel therapeutic approach for the treatment of liver disease associated with AAT deficiency, an increasingly recognized problem where there is significant unmet need. Our pre-clinical results, including new data presented at the DDW meeting, demonstrate that RNAi therapeutics targeting AAT can reduce liver levels of mutant AAT, improve histopathology associated with mutant AAT expression, and reduce liver fibrosis and the incidence of tumor formation in a mouse model of disease; additional data have been generated in non-human primates,” said Rachel Meyers, Ph.D., Vice President, Research and RNAi Lead Development at Alnylam. “We very much look forward to the continued advancement of this program toward the clinic, including the expected filing of an IND in mid-2015. As such, ALN-AAT is positioned to become our seventh program in clinical development by the end of 2015, consistent with the up-scaled “Alnylam 5x15” guidance that we provided earlier this year.”

As previously presented at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD, “The Liver Meeting”) in November 2013 and as updated at DDW, studies were performed in transgenic mice overexpressing the human Z-AAT protein. Subcutaneous administration of a GalNAc-siRNA conjugate targeting AAT (GalNAc-AAT) resulted in rapid, potent, dose-dependent, and durable knockdown of liver Z-AAT protein and improved liver histopathology as measured by reduced number of Z-AAT liver globules. As measured in serum samples, knockdown of human Z-AAT exceeded 95%. In addition, experiments were performed in aged mice (25-46 weeks old) with advanced, established liver disease; animals were treated with placebo or GalNAc-AAT administered by subcutaneous injection every other week for 18 weeks. GalNAc-AAT treatment resulted in significant (p < 0.05) improvement in liver pathology and function as evidenced by decreased levels of Col1a2 (a marker of fibrosis), PTPRC (a marker of immune cell infiltration), and BrdU incorporation (a measure of cell proliferation) relative to PBS-treated animals. Further, GalNAc-AAT treatment resulted in a significant reduction (p < 0.05) in the incidence of liver tumors associated with Z-AAT overexpression (1/6, 16.7%) when compared to those mice treated with PBS (4/6, 66.7%). Optimization of GalNAc-siRNA conjugates led to the selection of the final DC for the ALN-AAT program. The ALN-AAT DC employs Alnylam’s Enhanced Stabilization Chemistry (ESC) GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency, durability, and a wide therapeutic index. In rodent studies, ALN-AAT showed potent and dose-dependent knockdown of serum AAT with a single-dose ED50 of 0.5 mg/kg. In multi-dose rodent experiments, subcutaneous administration at 0.5 mg/kg resulted in approximately 90% knockdown of serum AAT. Finally, initial single-dose non-human primate studies were performed showing dose-dependent knockdown of serum AAT – a surrogate for AAT knockdown in the liver – with an ED50 of less than 3 mg/kg; these results are expected to support a multi-dose ED50 of less than 1 mg/kg, consistent with other ESC-GalNAc-siRNA conjugates.

“AAT deficiency-associated liver disease is caused by the mutant ‘Z allele’ of the AAT gene, whose protein misfolds, accumulates in liver cells, and causes cellular damage. People that are homozygous for the mutant Z allele make up approximately 95% of patients with AAT deficiency. These individuals have a lifetime risk of liver disease of 10% to 50%, which manifests as cholestatic disease, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Severe liver disease can occur in children and adults and is currently managed with supportive care, or in the case of liver failure, with liver transplantation. Clearly, there is a very high unmet need for novel therapies for AAT-deficient patients with liver disease,” said Jeffrey Teckman, M.D., Professor in the Department of Pediatrics and Director of Gastroenterology and Hepatology at Saint Louis University School of Medicine. “I am encouraged by the pre-clinical data with ALN-AAT, and if these results extend in clinical studies, I believe that this investigational RNAi therapeutic could become an important treatment option for the management of liver disease in people with AAT deficiency.”

About Alpha-1 Antitrypsin (AAT) and AAT Deficiency

Alpha-1 antitrypsin deficiency is an autosomal disorder that results in disease of the lungs and liver. AAT is a liver-produced serine proteinase inhibitor with the primary function of protecting the lungs from neutrophil elastase and other irritants that cause inflammation. In the liver, misfolding of the mutant Z-AAT protein hinders its normal release into the blood thereby causing it to aggregate in hepatocytes, leading to liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). A deficient serum level of the protein can render the lungs susceptible to emphysema. About 95% of people with alpha-1 antitrypsin deficiency are homozygous and carry two copies of the abnormal Z allele (PiZZ). There are estimated to be approximately 120,000 people who are PiZZ in the U.S. and major European countries, and of these, about 10% have an associated liver pathology caused by the misfolded protein encoded by the pathogenic Z-allele. Treatment for lung disease associated with AAT deficiency consists of routine emphysema care and, in some instances, augmentation therapy, which utilizes purified AAT from the plasma of healthy donors to increase circulating and airway levels of AAT to help restore its function in the lungs. The only treatment options presently available for patients with cirrhosis caused by mutant AAT accumulation in the liver are supportive care and, in the case of advanced cirrhosis, liver transplantation. RNAi-mediated inhibition of AAT in AAT-deficient PiZZ patients may represent a promising new way to treat this rare disease.

About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC) GalNAc Conjugates

GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam’s Enhanced Stabilization Chemistry (ESC) GalNAc-conjugate technology enables subcutaneous dosing with increased potency, durability, and a wide therapeutic index, and is being employed in several of Alnylam’s genetic medicine programs, including programs in clinical development.

About RNAi

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines with a core focus on RNAi therapeutics as genetic medicines, including programs as part of the company’s “Alnylam 5x15TM” product strategy. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; and other programs yet to be disclosed. As part of its “Alnylam 5x15” strategy, as updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development – including at least two programs in Phase 3 and five to six programs with human proof of concept – by the end of 2015. The company’s demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. In March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned subsidiary of Merck. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world’s top scientific journals such as NatureNature MedicineNature BiotechnologyCell, the New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

About “Alnylam 5x15™” and Genetic Medicines

The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics as genetic medicines. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of diseases with high unmet medical need. These programs share several key characteristics including: a genetically defined target and disease expressed in the liver; the potential to have a major impact in a high unmet need population; the ability to leverage the existing Alnylam RNAi platform with clinically proven delivery to the liver; the opportunity to monitor an early biomarker in Phase 1 clinical trials for human proof of concept; and the existence of clinically relevant endpoints for the filing of a new drug application (NDA) with a focused patient database and possible accelerated paths for commercialization. As updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development – including at least two programs in Phase 3 and five to six programs with human proof of concept – by the end of 2015. The “Alnylam 5x15” programs include: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR in development for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) in development for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) in development for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 in development for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 in development for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, a subcutaneously administered RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; and other programs yet to be disclosed. In 2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic alliance on Alnylam’s genetic medicine programs. Specifically, Alnylam will lead development and commercialization of programs in North America and Europe, while Genzyme will develop and commercialize products in the rest of world. In addition, Alnylam and Genzyme will co-develop and co-commercialize ALN-TTRsc in North America and Europe.

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